The goal of the Center for the Study of Reproductive Biology and Disease will be do develop understanding of the mechanisms which govern normal and disordered function of the hypothalamic-pituitary- ovarian axis. We will continue to produce novel and important contributions os the reproductive sciences, integrating multi- disciplinary clinical and basic research to facilitate and accelerate the translation of promising new discoveries into clinical medicine. We have chosen five innovative research projects, all with experienced, internationally renowned leaders. Research project 11 will investigate the molecular mechanisms of gene regulation in the gonadotrope with specific focus on responses to GnRH and the activin/follistatin system and their interactions. Research project 12 will chart new territory in the role of the oocyte in follicular maturation studying GDF-9 in both rat and human ovaries. Research Project 13 will provide detailed molecular understanding of the signal transduction cascade of GnRH. Analyses will include the roles of G proteins both alpha and Betagamma subunits, the role of MAP kinase and ras, and differential use signaling pathways for various actions of GnRH in the gonadotrope. Research Project 14 will investigate the roles of the Bone Morphogenetic Proteins, members of the TGF-Beta superfamily, in ovarian physiology. Emphasis will be placed on testing the new hypothesis that BMPs are luteinization inhibitors and their activities are regulated by follistatin. Analyses will include cultured rat and human granulosa cells and rats in vivo. Research project 15 will focus on the influence of insulin in the endocrine control of LH release and steroid synthesis by the ovarian granulosa and theca compartments in vivo in normal women and patients with polycytic ovary syndrome. Two closed Cored are proposed: the Administrative Core and the Recombinant Protein Core. The Administrative Core will provide administrative, fiscal, planning and meeting services and administer the Enrichment Program. The Recombinant Protein Core will meet the needs of the Research Projects for production, purification and characterization of proteins and antibodies that are unavailable elsewhere. We envision that this integrated research Center will generate a repertoire of discoveries that will provide a comprehensive understanding of the molecules, cells, and systems involved in controlling reproductive function, leading to improved treatment of disease.